juvenile idiopathic arthritis in adulthood fulfilment of classification criteria for adult rheumatic diseases long term outcomes and predictors of inactive disease functional status and damage

ORIGINAL ARTICLEJuvenile idiopathic arthritis in adulthood: adult rheumatic diseases, long-term outcomes and predictors of inactive disease, functional status and damage Filipa Oliveira-

ORIGINAL ARTICLE

Juvenile idiopathic arthritis in adulthood:

adult rheumatic diseases, long-term outcomes and predictors of inactive disease, functional status and damage

Filipa Oliveira-Ramos,1,2Mónica Eusébio,3Fernando M Martins,3 Ana Filipa Mourão,2,4 Carolina Furtado,5Raquel Campanilho-Marques,1,2 Inês Cordeiro,6Joana Ferreira,7Marcos Cerqueira,8Ricardo Figueira,9Iva Brito,10 Helena Canhão,1,2Maria José Santos,2,6José A Melo-Gomes,11

João Eurico Fonseca1,2

To cite: Oliveira-Ramos F,

Eusébio M, M Martins F,

et al Juvenile idiopathic

arthritis in adulthood:

fulfilment of classification

criteria for adult rheumatic

diseases, long-term outcomes

and predictors of inactive

disease, functional status and

e000304 doi:10.1136/

rmdopen-2016-000304

additional material is

available To view please visit

the journal (http://dx.doi.org/

10.1136/rmdopen-2016-000304).

Received 27 April 2016

Revised 4 July 2016

Accepted 5 July 2016

For numbered affiliations see

end of article.

Correspondence to

Dr Filipa Oliveira-Ramos;

filipa.o.ramos@gmail.com

ABSTRACT Objectives:To determine how adult juvenile idiopathic arthritis ( JIA) patients fulfil classification criteria for adult rheumatic diseases, evaluate their outcomes and determine clinical predictors of inactive disease, functional status and damage.

Methods:Patients with JIA registered on the Rheumatic Diseases Portuguese Register (Reuma.pt) older than 18 years and with more than 5 years of disease duration were included Data regarding sociodemographic features, fulfilment of adult classification criteria, Health Assessment Questionnaire, Juvenile Arthritis Damage Index —articular ( JADI-A) and Juvenile Arthritis Damage Index —extra-articular ( JADI-E) damage index and disease activity were analysed.

Results:426 patients were included Most of patients with systemic JIA fulfilled criteria for Adult Still ’s disease 95.6% of the patients with rheumatoid factor (RF)-positive polyarthritis and 57.1% of the patients with RF-negative polyarthritis matched criteria for rheumatoid arthritis (RA) 38.9% of the patients with extended oligoarthritis were classified as RA while 34.8% of the patients with persistent oligoarthritis were classified as spondyloarthritis Patients with enthesitis-related arthritis fulfilled criteria for spondyloarthritis in 94.7% Patients with psoriatic arthritis maintained this classification Patients with inactive disease had lower disease duration, lower diagnosis delay and corticosteroids exposure Longer disease duration was associated with higher HAQ, JADI-A and JADI-E Higher JADI-A was also associated with biological treatment and retirement due to JIA disability and higher JADI-E with corticosteroids exposure Younger age at disease onset was predictive

of higher HAQ, JADI-A and JADI-E and decreased the chance of inactive disease.

Key messages

What is already known about this subject?

▸ Many patients with juvenile idiopathic arthritis ( JIA) are followed into adulthood and frequently have their diagnosis freely reclassified using adult rheumatic diseases terminology.

▸ There is no published data on how adult patients with JIA fulfil classification criteria of adult rheumatic diseases, and very scarce information

is available, especially in the postbiological treat-ments era, on functional status, damage and social outcomes, such as education and profes-sional activity.

What does this study add?

▸ Our study is one of the longest and largest studies evaluating JIA in adulthood and was the first to evaluate how adult patients with JIA fulfil classification criteria for adult rheumatic dis-eases and to apply to these patients, activity scores validated for adult diseases.

How might this impact on clinical practice?

▸ We believe that understanding the way these juvenile diseases progress could add useful information for the ongoing discussion of a new classification capable of better unifying the lan-guage between paediatric and adult care and to contribute to a better understanding of the long-term outcomes and consequences of the current treatment regimes used in JIA.

▸ In our view, these results will be of interest to paediatric and adult rheumatologists who are involved in the clinical care of patients with JIA.

Conclusions:Most of the included patients fulfilled classification

criteria for adult rheumatic diseases, maintain active disease and

have functional impairment Younger age at disease onset was

predictive of higher disability and decreased the chance of inactive

disease.

INTRODUCTION

The global burden of juvenile idiopathic arthritis ( JIA)

is difficult to be accurately established Inconsistencies

on classification and on evaluation of disease activity and

loss of follow-up due to remission or change of medical

care from paediatric into adult rheumatology have

con-tributed to incomplete understanding of the adult

impact of JIA

Many patients with JIA are followed into adulthood

Indeed, in the Rheumatic Diseases Portuguese Register

(Reuma.pt), 56% of the patients with JIA on follow-up

have reached adulthood.1 2 Frequently, these patients

have their diagnosis freely reclassified using adult

rheumatic diseases terminology However, there is no

published data on how adult patients with JIA fulfil

clas-sification criteria of adult rheumatic diseases In

add-ition, very scarce information is available, especially in

the postbiological treatments era, on functional status,

damage and social outcomes, such as education and

professional activity, of adults who are affected by these

childhood-onset diseases

Portugal offers an opportunity niche due to the

exist-ence of several institutions with an integrated follow-up,

first of patients with juvenile rheumatic disease and

then, later on, of adults with juvenile onset rheumatic

conditions Moreover, the Reuma.pt has the unique

feature of having a complete integration of juvenile

patients, assessed by validated tools, in the overall

data-base, thus greatly facilitating the tracking of the

transi-tion into adulthood.1

By exploring this unique research opportunity, our

aim was to determine how adult patients with JIA

ful-filled classification criteria of adult rheumatic diseases,

evaluate their disease activity, damage, functional and

social outcomes and determine clinical predictors of

inactive disease, poor functional status and damage

MATERIALS AND METHODS

Study design and patient selection

This is a cross-sectional analysis nested in a cohort study

with the following inclusion criteria: patients with JIA

according to the 2001 revised International League of

Associations for Rheumatology (ILAR) criteria,3

regis-tered in Reuma.pt, that at the time of data analysis

(October 2015) were older than 18 years, had a disease

duration of >5 years and available data in adulthood

The Reuma.pt was developed by the Portuguese

Society of Rheumatology, became active in June 2008

and includes patients with adult rheumatoid arthritis

(RA), spondyloarthritis (SpA), JIA, systemic lupus

erythematosus (SLE) and several other rheumatic dis-eases It covers mainland Portugal, Madeira and Azores islands, involving over 70 centres and having included

up to now more than 15 000 patients, with more than

112 000 medical appointments registered Specifically,

1563 patients who had JIA with 11 828 medical visits have been registered so far.2

At the time of this analysis, a total of 889 adult patients with JIA were registered in Reuma.pt For 150 of these adult patients, there were no data registered in adult-hood and they were excluded Of the 739 patients eli-gible for this study, only 426 had complete data registered, by their attending rheumatologist, regarding ILAR category at onset and were included From these

426 patients, 71 patients were registered in childhood and 355 patients were introduced in Reuma.pt already

in adulthood and classified retrospectively according to the ILAR classification Disease onset was defined by the date on which a physician first documented arthritis Data before 2008 was registered retrospectively and from that date prospectively

Registry of patient data in Reuma.pt was performed after signed informed consent was obtained This study was approved by the scientific committee of Reuma.pt and by the ethics committee of Lisbon Academic Medical Centre Reuma.pt was approved by the National Committee for Data Protection and by local ethics com-mittees of the participating centres The study was con-ducted according to the Declaration of Helsinki

Clinical assessment The following information registered in Reuma.pt at the time of patient’s last visit was obtained: gender, ethnicity, age at last visit, years of education, employment status (employed, unemployed, retired and retired due to JIA induced disability), ILAR category at onset, age at disease onset, disease duration (years), presence of rheumatoid factor (RF), anticitrullinated protein anti-bodies (ACPA), antinuclear antianti-bodies (ANAs; consid-ered positive if titres ≥1/160) and human leucocyte antigen (HLA) B27, number of swollen/tender joints, patient and physician’s global assessment of disease activity (0–10), back pain (0–10), morning stiffness intensity (0–10), erythrocyte sedimentation rate (ESR, mm/first hour) and C reactive protein level (CRP, mg/ dL), extra-articular manifestations, Health Assessment Questionnaire (HAQ), Juvenile Arthritis Damage Index ( JADI), current and previous therapy with corticoster-oids, disease-modifying antirheumatic drugs (DMARDs) and biological therapy In the Reuma.pt JIA protocol, there is afield asking the physician to check if the adult patient fulfils classification criteria for any of the follow-ing adult rheumatic diseases: RA; ankylosfollow-ing spondylitis (AS); psoriatic arthritis (PsA); undifferentiated spondy-loarthritis (USpA); arthropathy of inflammatory bowel disease; adult Still disease (ASD)—persistent systemic, ASD—polyarticular course after systemic onset; non-classifiable Data registered in this Reuma.pt field were

also exported The information needed to verify classi

fi-cation criteria for RA (2010 ACR/EULAR)4, AS (1984

modified New York criteria)5 and PsA (CASPAR

cri-teria)6is specifically asked for in Reuma.pt

Juvenile Arthritis Disease Activity Score ( JADAS)7

shows limitations for the assessment of adults with JIA,

particularly those with predominant axial disease For

that reason, we opted to apply disease activity scores

spe-cific for adult diseases In this way, disease activity at the

time of Reuma.pt last visit was assessed through

disease-specific activity indexes according to the adult rheumatic

disease: Disease Activity Score (DAS) 28 for patients

clas-sified as RA, DAS 44 for PsA and peripheral SpA and AS

Disease Activity Score (ASDAS) for AS Patients were

classified as having inactive disease based on cut-offs

defined for each index: DAS 28<2.6;8–10DAS 44<1.6;11 12

ASDAS <1.3.13 Patients classified as ASD or with

non-classifiable adult rheumatic disease were considered to

have inactive disease if they had no active arthritis; no

fever, rash, serositis, splenomegaly or generalised

lymph-adenopathy attributable to JIA; no active uveitis; normal

ESR and/or CRP; a physician’s global assessment of

disease activity rated at the best score possible.14

Functional status was measured by HAQ,15obtained in

the last visit For the purpose of this analysis, mild

dis-ability was considered for HAQ scores >0 and≤0.5,

mod-erate disability >0.5 and≤1.5 and severe disability >1.5.16

Radiographs do not fully reflect the structural

outcome of JIA, because they represent mainly cartilage

and osseous changes, whereas part of the articular

damage in JIA is in the soft tissues surrounding the

bones This extra-articular damage is not measured by

the radiographic scores validated in JIA.17–19 The

evalu-ation of JIA damage into adulthood lacks validevalu-ation for

radiographic assessment and for JADI application In

the absence of a validated score for adults with JIA, we

opted to use JADI, as a more comprehensive way of

assessing articular damage ( JADI-A) and extra-articular

damage ( JADI-E).20

Statistical analyses

Continuous covariates were expressed in terms of their

mean and SD Categorical covariates were described by

frequency distribution

Comparisons between groups of the covariates and

the outcomes were evaluated using univariated linear

regression for continuous response variables and

uni-variated logistic regression for binary response variables

After assessing the differences, multivariate logistic or

linear regression models were used to examine the

asso-ciation, adjusted for ILAR category, of a range of

demo-graphic and clinical variables with the following

outcomes: HAQ, JADI-A and JADI-E as continuous

vari-ables and disease activity as a dichotomous variable In

order to compare the outcomes before and after

bio-logical era, we used multivariate logistic or linear

regres-sion analysis adjusted for ILAR category and disease

duration

In order to obtain the predictor models, we used three multivariable linear regression models for the con-tinuous outcomes (HAQ, JADI-A, JADI-E) and one multivariate logistic regression model for the dichotom-ous outcome, by a stepwise selection method

Missing data were interpreted as random missing data

In all analyses, significance level was set at 0.05

All analyses were performed using Stata IC V.12 (StataCorp 2011 Stata Statistical Software: Release 12 College Station, Texas: StataCorp LP)

RESULTS Patient characteristics

A total of 426 patients were included in the study, whose main demographic and clinical features are shown in table 1

The mean age at the last registered visit was 34.1

±12.8 years, and the mean disease duration was 22.5

±12.4 years Most of the patients (84.3%) had disease duration longer than 10 years, and 24.2% exceeded

30 years Only 18.5% of the patients had persistent oli-goarthritis, and JIA categories with polyarticular involve-ment and enthesitis-related arthritis (ERA) were the most prevalent ones, affecting 45.6% and 18.8% of the patients, respectively Systemic-onset JIA (SoJIA) was found in 9.6% of the patients, PsA in 3.1% and undiffer-entiated arthritis in 1.4% of the patients The prevalence

of ANA, RF, ACPA and HLA B27 are shown in table 1 with random missed data that were not related to any specific clinical attitude

This was a predominantly professionally active popula-tion (71.9% of the patients employed), with a mean 11.6 years of education Almost 13% were retired due to JIA disability

Most of the studied patients (67%) still had active disease, and 71.9% were on a synthetic or biological DMARD Furthermore, 36.4% of the patients with inactive disease were off medication Most of the patients (65.5%) had no or mild HAQ disability, and 11% had severe disability

Fulfilment of classification criteria for adult rheumatic diseases

Data regarding fulfilment of classification criteria for adult rheumatic diseases (table 2) revealed that 92.3%

of the patients with SoJIA could be classified as ASD, 58.3% with persistent systemic features and 41.6% with polyarticular predominant involvement Furthermore, 95.6% of the patients with RF-positive polyarthritis and 57.1% of the patients with RF-negative polyarthritis ful-filled criteria for RA The remaining patients with RF-negative polyarthritis could not be classified in 23.8%

of the cases, and 12.7% of the patients were classified as PsA The patients with persistent oligoarthritis were

clas-sified into several adult rheumatic diseases, with 34.8% classified as SpA, which included enteropathic arthritis

in 6% of the cases Only 13% of these patients had HLA

B27 and 21.7% were ANA-positive Furthermore, 59.1%

of the patients who had persistent oligoarthritis remain unclassified, as well as 35.2% of the patients with extended oligoarthritis Most of the patients with extended oligoarthritis were classified as RA (38.9%) or SpA (26%) Patients with ERA fulfilled criteria for any form of SpA in 94.7% All patients with PsA maintained this classification For 21% of the patients, it was impos-sible to classify them in any adult rheumatic disease This adult unclassified population come mainly from RF-negative polyarticular and oligoarticular (mostly per-sistent oligoarticular) categories

Disease activity, functional status and damage Disease activity, HAQ, JADI and retirement due to JIA dis-ability according to ILAR categories are shown intable 3 There was no significant association in univariate ana-lysis between current disease activity and baseline vari-ables such as ILAR category at onset, ANA and RF In multivariate analysis adjusted for ILAR category, inactive disease was associated with shorter disease duration (OR=0.95; 95% CI 0.9 to 1.0; p value<0.001), less diag-nosis delay (OR=0.9; 95% CI 0.9 to 1.0; p value=0.017), lower HAQ (OR=0.1; 95% CI 0.1 to 0.2; p value<0.001) and less corticosteroid exposure (OR=1.0; 95% CI 0.99

to 1.00; p value=0.019), as shown intable 4

In univariate analysis, there was a positive association with higher HAQ in patients with extended oligoarticular (β=0.3; 95% CI 0.1 to 0.5; p value=0.006), polyarticular RF-positive (β=0.5; 95% CI 0.3 to 0.8; p value<0.001) and polyarticular RF-negative (β=0.4; 95% CI 0.1 to 0.6; p value=0.001), when comparing with persistent oligoarti-cular category After adjustment to ILAR category, higher HAQ was associated with longer disease duration (β=0.03; 95% CI 0.02 to 0.03; p value<0.001) and exposure to bio-logical treatments (β=0.2; 95% CI 0.04 to 0.3; p value=0.014) The persistence of systemic features was associated with lower HAQ (β=−0.6; 95% CI −1.0 to −0.2;

p value=0.003), while RA classification was associated with higher HAQ (β=0.5; 95% CI 0.3 to 0.7; p value<0.001), when comparing to adult non-classifiable forms (table 5) JADI-A and JADI-E were available in only 140 (32.8%) and 111 (26%) patients, respectively We only included

in JADI analysis patients with these data available In uni-variate analysis, patients with RF-positive polyarthritis (β=17.5; 95% CI 8.1 to 26.8; p value<0.001), RF-negative polyarthritis (β=8.8; 95% CI 1.6 to 16.0; p value=0.018) and SoJIA (β=12.2; 95% CI 2.8 to 21.5; p value=0.011) had higher association with JADI-A when comparing to patients with persistent oligoarthritis After adjustment for ILAR category, retired patients due to JIA disability had higher JADI-A scores than employed patients (β=29.1; 95% CI 19.9 to 38.3; p value<0.001) Longer disease duration (β=0.3; 95% CI 0.1 to 0.5;

p value=0.001) and past or current biological treatment (β=6.9; 95% CI 1.3 to 12.5; p value=0.016) were also associated with higher JADI-A scores, after adjustment for ILAR category (table 5)

Table 1 Characteristics of the 426 study patients

Variables

No (%)/

Mean±SD Female 288 (67.6%)

Male 138 (32.3%)

JIA ILAR category

Persistent oligoarthritis 79 (18.5%)

Extended oligoarthritis 61 (14.3%)

RF-positive polyarthritis 71 (16.7%)

RF-negative polyarthritis 75 (17.6%)

Systemic 41 (9.6%)

Enthesitis-related arthritis 80 (18.8%)

Psoriatic arthritis 13 (3.1%)

Undifferentiated arthritis 6 (1.4%)

Age at disease onset (years) (n=423) 9.9±4.8

Age at diagnosis (years) (n=399) 14.4±9.9

Age at the time of last registered visit

(years)

34.1±12.8 Disease duration (years) (n=423) 22.5±12.4

ANA+ (n=244) 75 (30.7%)

RF + (n=320) 88 (27.5%)

ACPA + (n=121) 37 (30.8%)

HLA B27 + (n=189) 75 (30.7%)

Years of education (n=234) 11.6±3.7

Current professional situation (n=234)

Employed 168 (71.8%)

Unemployed 24 (10.3%)

Retired 11 (4.7%)

Retired due to JIA disability 31 (13.2%)

Disease activity (n=300)

Active disease 201 (67%)

Inactive disease 99 (33%)

HAQ Score (n=426) 0.5±0.7

JADI-A Score (n=140) 7.7±14.5

JADI-E Score (n=111) 0.8±1.6

Past treatment

Patients who had received

corticosteroids (n=399)

80 (20%) Patients who had received synthetic

DMARDs (n=399)

84 (21%) Patients who had received biological

DMARDs (n=399)

31 (7.8%) Current treatment

Patients who were on corticosteroids

(n=399)

103 (25.8%) Patients who were on synthetic

DMARDs (n=399)

245 (61.4%) Patients who were on biological

DMARDs (n=399)

140 (35.1%) Cumulative corticosteroid exposure (years)

(n=175)

8.3±8.9 Cumulative synthetic DMARDs exposure

(years) (n=326)

10.6±9.5 Cumulative biological DMARDs exposure

(years) (n=173)

6.1±3.7

ACPA, anticitrullinated protein antibodies; ANAs, antinuclear

antibodies; DMARDs, disease-modifying antirheumatic drugs;

HAQ, Health Assessment Questionnaire; ILAR, International

League of Associations for Rheumatology; JADI-A, Juvenile

RF, rheumatoid factor.

Worse JADI-E was associated with longer disease

dur-ation (β=0.04; 95% CI 0.02 to 0.06; p value=0.001) and

corticosteroids exposure (β=1.2; 95% CI 0.5 to 1.9; p

value=0.001), after adjustment for ILAR category The

severity of extra-articular damage was similar across the

different JIA categories and had no association to the

different adult rheumatic diseases each patient fulfilled

criteria for (table 5)

In order to assess the differences between outcomes

of patients with disease onset before and after the

bio-logical era, we compared the outcomes of patients with

disease onset before and after 2001 After adjustment

for ILAR category and for disease duration, we found no

differences between inactive disease, HAQ and JADI in

both groups (see online supplementary table S1)

Predictors of inactive disease, poor functional status and

damage

For inactive disease, a multivariate logistic stepwise

regression model was used Clinical variables were

selected regarding their statistical and clinical relevance

(table 6) Older age at disease onset increased the

chance of inactivity of disease at the last registered visit (OR=1.4; 95% CI 1.1 to 1.8; p=0.008) ACPA positivity decreased the likelihood of disease inactivity by 93.1% (OR=0.07; 95% CI 0.01 to 0.7; p=0.028)

Predictors of poor functional status were analysed by a multivariate linear stepwise regression model, and we found that younger age at disease onset was the only vari-able that could predict higher HAQ scores in adulthood (β=−0.02; 95% CI −0.04 to −0.00; p=0.021) Younger age

at disease onset was also associated with higher JADI-A (β=−0.9; 95% CI −1.4 to −0.3; p=0.003) and JADI-E (β=

−0.1; 95% CI −0.2 to −0.03; p=0.008) RF-positive polyar-thritis (β=16.20; 95% CI 6.78 to 25.63; p=0.001) and SoJIA (β=10.2; 95% CI 1.0 to 19.3; p=0.029) were predict-ive of worse JADI-A, using persistent oligoarthritis as ref-erence Corticosteroid exposure was also predictive of worse JADI-E (β=1.1; 95% CI 0.4 to 1.9; p=0.002)

DISCUSSION This is a long-term follow-up study of patients with JIA (mean disease duration of 22.5±12.4 years), with 24.2%

of the patients having more than 30 years of disease

Table 2 Classification according to adult rheumatic diseases

Onset ILAR category

Adult rheumatic disease classification at the last visit

RA AS USpA EA PsA ASD Non-classifiable Systemic, n=39 2 (5.1%) 0 0 0 0 36 (92.3%) 1 (2.6%)

RF − poly, n=63 36 (57.1%) 2 (3.8%) 2 (3.8%) 0 8 (12.7%) 0 15 (23.8%) RF+ poly, n=68 65 (95.6%) 1 (1.5%) 0 0 1 (1.5%) 0 1 (1.5%)

P oligo, n=66 4 (6.1%) 5 (7.6%) 9 (13.6%) 4 (6.1%) 5 (7.6%) 0 39 (59.1%)

E oligo, n=54 21 (38.9%) 2 (3.7%) 10 (18.5%) 1 (1.9%) 1 (1.9%) 0 19 (35.2%) ERA, n=76 0 41 (53.9%) 21 (27.6%) 4 (5.3%) 6 (7.9%) 0 4 (5.3%)

PsA, n=13 0 0 0 0 12 (92.3%) 0 1 (7.7%)

Undif, n=6 3 (50%) 1 (16.7%) 0 1 (16.7%) 0 0 1 (16.7%) Total 131 (34%) 52 (13.5%) 42 (10.9%) 10 (2.6%) 33 (8.6%) 36 (9.4%) 81 (21%)

AS, ankylosing spondylitis; ASD, adult Still disease; E Oligo, extended oligoarthritis; EA, enteropathic arthritis; ERA, enthesitis-related

arthritis; ILAR, International League of Associations for Rheumatology; JIA, juvenile idiopathic arthritis; P Oligo, persistent oligoarthritis; PsA,

polyarthritis; Undif, undifferentiated arthritis; USpA, undifferentiated spondyloarthritis.

Table 3 Disease activity, HAQ Score, JADI Score and retirement due to JIA disability, according to ILAR subgroups

ILAR category

Disease activity, active/inactive HAQ Score* JADI-A Score* JADI-E Score*

Patients retired due to JIA (%)

P oligoarthritis 34/22 (n=56) 0.26±0.4 (n=79) 0.8±1.4 (n=26) 0.2±0.7 (n=19) 1 (2.9) (n=34)

E oligoarthritis 39/10 (n=49) 0.58±0.8 (n=61) 7.6±15 (n=22) 0.7±1.3 (n=18) 8 (25.8) (n=31) RF+ polyarthritis 36/14 (n=50) 0.80±0.7 (n=71) 18.3±17.6 (n=13) 0.7±1.4 (n=9) 11 (22)

(n=50)

RF − polyarthritis 39/19 (n=58) 0.61±0.7 (n=75) 9.6±15.2 (n=33) 1.3±2.3 (n=28) 6 (13.6) (n=44) SoJIA 20/12 (n=32) 0.43±0.6 (n=41) 13±21.8 (n=13) 1.2±1.9 (n=9) 0 (n=15) ERA 28/18 (n=46) 0.45±0.7 (n=80) 5.5±12.2 (n=31) 0.7±1.2 (n=26) 3 (6.3) (n=48) PsA 5/4 (n=9) 0.40±0.4 (n=13) 0±0 (n=2) 0±0 (n=2) 1 (16.6) (n=6) Undif arthritis n=0 0.69±0.2 (n=6) n=0 n=0 1 (16.6) (n=6)

*Values are mean±SD.

E oligoarthritis, extended oligoarthritis; ERA, enthesitis-related arthritis; HAQ, Health Assessment Questionnaire; ILAR, International League

of Associations for Rheumatology; JADI, Juvenile Arthritis Damage Index; JIA, juvenile idiopathic arthritis; P oligoarthritis, persistent

oligoarthritis; PsA, psoriatic arthritis; RF+ polyarthritis, rheumatoid factor negative polyarthritis; RF+ polyarthritis, rheumatoid factor positive polyarthritis; SoJIA, systemic onset juvenile idiopathic arthritis; Undif arthritis, undifferentiated arthritis.

duration There are only a limited number of published

studies with such a long follow-up period,21–23 but

describing smaller JIA cohorts and most of them

reported before biological therapy become available In

order to reflect the current long-term outcome of JIA,

studies should include patients who had the opportunity

to be treated with biological therapy if they had

indica-tion for receiving it In our study, this occurred at least

in 25% of the patients who had their disease onset after

2001 On the other hand, an adult population should be

evaluated regarding disease activity with tools validated

in adult population, according to their current

rheum-atic condition For example, it is not suitable to evaluate

the disease activity of a patient with JIA who evolved, in

adulthood, to a predominantly axial SpA, with JADAS,7

as this index does not reflect axial activity and is not

vali-dated in adults In fact, even in children with ERA,

JADAS should be better evaluated, as validation in this

JIA subtype has involved very few patients.24

In our study, we found that most of the patients were

still on non-biological or biological DMARD and 67%

have disease activity, which contrast with a lower activity

profile depicted in other long-term studies Selvaag

et al21 reported that 41% of the patients with JIA

main-tained disease activity after 30 years and other studies

reported active disease in 37–43% of the patients.22

However, these studies were based on different disease

activity parameters Studies with shorter follow-up

period25 26 reported rates of disease activity similar to

ours (50–67%), but again different parameters were

used to measure disease activity The tools to measure disease activity that we applied were chosen according to current adult rheumatic disease classification, and they might be more sensitive to detect disease activity in an adult population This could be particularly relevant in patients with predominant axial involvement, as the ones classified as AS, who represent 13.5% of this popu-lation Another possible reason for this high percentage

of patients with active disease is because JIA categories with better outcomes, as persistent oligoarthritis, are under-represented in this study, as many go into remis-sion and do not require any treatment neither adult rheumatology care On the other hand, patients treated with biologics might be overrepresented in these type of registries and this might be reflected, for instance by a higher percentage of patients with RF-positive polyarthritis

To the best of our knowledge, this is the first long-term follow-up study to evaluate how adult patients with JIA fulfilled classification criteria for adult rheumatic dis-eases Only 21% of the patients were unclassifiable in any adult rheumatic disease This percentage could have been higher if the oligoarticular-onset categories would have been more represented in this study We found that patients with RF-positive polyarthritis onset could be classified in 95.6% of the cases as RA and 94.7% of the patients with ERA as SpA Regarding patients with SoJIA, it was also clear that in adulthood they could be classified as ASD and all juvenile-onset PsA maintained the diagnosis of PsA in adulthood Thus, for these

Table 4 Associations between variables collected at patient ’s last visit and current disease activity

Variables

Active disease Inactive disease

OR (95% CI) p Value OR (95% CI) p Value Age of disease onset* 1.0 (0.9 to 1.0) 0.186 1.0 (1.0 to 1.1) 0.186 Disease duration* 1.1 (1.0 to 1.1) <0.001 † 1.0 (0.9 to 1.0) <0.001 † Delay in diagnosis* 1.1 (1.0 to 1.1) 0.017 † 0.9 (0.9 to 0.9) 0.017 † ANA* 0.9 (0.4 to 1.8) 0.682 1.2 (0.5 to 2.5) 0.682 RF* 1.5 (0.5 to 4.2) 0.472 0.7 (0.2 to 2.0) 0.475 B27* 1.5 (0.5 to 5.1) 0.481 0.6 (0.2 to 2.2) 0.481 ACPA* 2.5 (0.5 to 11.8) 0.239 0.4 (0.1 to 1.8) 0.239 Years of education* 1.0 (0.9 to 1.1) 0.686 1.0 (0.9 to 1.1) 0.686 Professional activity* ‡

Unemployed 0.6 (0.2 to 1.9) 0.352 1.8 (0.5 to 5.8) 0.352

Retired due to JIA disability 3.0 (0.8 to 1.9) 0.118 0.3 (0.1 to 1.3) 0.118 HAQ score* 9.1 (4.1 to 20.2) <0.001 † 0.1 (0.1 to 0.2) <0.001 † Duration of corticosteroid therapy* 1.0 (1.0 to 1.0) 0.019 † 1.0 (1.0 to 1.0) 0.019 † Exposure to corticosteroids* 1.6 (0.9 to 2.9) 0.077 0.6 (0.3 to 1.1) 0.077 Exposure to biological DMARDs* 1.3 (0.7 to 2.2) 0.375 0.8 (0.4 to 1.4) 0.375 Exposure to synthetic DMARDs* 0.8 (0.4 to 1.6) 0.552 1.2 (0.6 to 2.4) 0.552

†p Value<0.05.

*Adjusted for ILAR Category.

‡Compared to employed.

ACPA, anticitrullinated protein antibodies; ANAs, antinuclear antibodies; AS, ankylosing spondylitis; ASD, adult Still disease; DMARDs, disease-modifying antirheumatic drugs; E oligoarthritis, extended oligoarthritis; EA, enteropathic arthritis; ERA, enthesitis-related arthritis; ILAR, International League of Associations for Rheumatology; JIA, juvenile idiopathic arthritis; PsA, psoriatic arthritis; RA, rheumatoid arthritis;

RF, rheumatoid factor; RF+ polyarthritis, rheumatoid factor negative polyarthritis; RF+ polyarthritis, rheumatoid factor positive polyarthritis; SoJIA, systemic-onset juvenile idiopathic arthritis; Undif arthritis, undifferentiated arthritis; USpA, undifferentiated spondyloarthritis.

conditions, it seems acceptable to group in common

designations juvenile and adult onset patients However,

it is less clear-cut how the oligoarticular and

polyarticu-lar RF-negative forms evolve into adulthood In addition,

for undifferentiated JIA category, that had a low

prevalence in this study probably due to the long-term follow-up that reduces diagnosis uncertainty, no possible conclusions can be drawn on its evolution in adulthood The degree of disability in our patients mirrored the ones found in other recent studies of adult outcomes in

Table 5 Associations between variables collected at patient ’s last visit, HAQ and JADI

Variables

β (95% CI) p Value β (95% CI) p Value β (95% CI) p Value ILAR category*

E oligoarticular 0.3 (0.1 to 0.5) 0.006 † 6.8 ( −1.2 to 14.7) 0.094 0.5 ( −0.5 to 1.6) 0.335 RF+ polyarticular 0.5 (0.3 to 0.8) <0.001 † 17.5 (8.1 to 16.8) <0.001 † 0.5 ( −0.8 to 1.7) 0.484 RF-poly articular 0.4 (0.1 to 0.6) 0.001 † 8.8 (1.6 to 16.0) 0.018 † 1.1 (0.2 to 2.1) 0.022 † Systemic 0.2 ( −0.1 to 0.4) 0.193 12.2 (2.8 to 21.5) 0.011 † 1.0 ( −0.3 to 2.3) 0.123 ERA 0.2 ( −0.0 to 0.4) 0.077 4.7 ( −2.6 to 12.0) 0.208 0.4 ( −0.5 to 1.4) 0.363 PsA 0.1 ( −0.2 to 0.5) 0.480 −0.8 (−21.0 to 19.3) 0.934 −0.2 (−2.6 to 2.2) 0.860 Undiff arthritis 0.4 ( −0.1 to 1.0) 0.130 NA NA NA NA Adult rheumatic disease ‡§

PsA 0.2 ( −0.1 to 0.5) 0.194 1.5 ( −13.2 to 16.1) 0.844 0.1 ( −1.7 to 1.9) 0.913

RA 0.5 (0.3 to 0.7) <0.001 † 4.4 ( −3.6 to 12.4) 0.275 0.5 ( −0.6 to 1.6) 0.358 ASD —systemic

persistent

−0.6 (−1.0 to −0.2) 0.003 † NA NA −0.8 (−3.1 to 1.4) 0.448 ASD —polyarticular

predominant

NA NA 17.2 (2.1 to 32.3) 0.026 † NA NA USpA 0.0 ( −0.3 to 0.3) 0.965 −1.8 (−12.2 to 8.5) 0.729 −0.2 (−1.6 to 1.2) 0.752

AS 0.3 (0.4 to 0.6) 0.024 † −0.2 (−10.2 to 9.8) 0.971 0.5 ( −0.9 to 1.8) 0.466

EA −0.0 (−0.5 to 0.4) 0.882 −3.6 (−19.8 to 12.6) 0.663 −0.4 (−2.9 to 2.1) 0.752 Age at disease

onset ‡ −0.0 (−0.0 to 0.0) 0.767 −0.7 (−1.3 to −0.2) 0.010† −0.1 (−0.1 to 0.0) 0.095 Disease duration ‡ 0.0 (0.0 to 0.0) <0.001 † 0.3 (0.1 to 0.5) 0.001 † 0.0 (0.0 to 0.1) 0.001 † Delay in diagnosis ‡ 0.0 (0.0 to 0.0) <0.001 † −0.0 (−0.3 to 0.2) 0.787 −0.0 (−0.1 to 0.0) 0.157 ANA ‡ 0.0 ( −0.1 to 0.2) 0.732 6.0 ( −1.2 to 13.3) 0.102 1.1 (0.1 to 2.1) 0.033 †

RF ‡ 0.1 ( −0.2 to 0.4) 0.606 −1.5 (−11.9 to 8.8) 0.772 −0.2 (−1.8 to 1.3) 0.784 B27 ‡ 0.0 ( −0.2 to 0.3) 0.748 −6.6 (−15.2 to 2.0) 0.132 −0.5 (−1.5 to 0.5) 0.286 ACPA ‡ 0.2 ( −0.3 to 0.7) 0.398 −3.5 (−31.9 to 24.9) 0.804 4.1×10−15( −6.1 to 6.1) ≈1 Professional activity ‡¶

Unemployed 0.0 ( −0.3 to 0.3) 0.904 1.1 ( −7.8 to 10.0) 0.811 1.0 ( −0.5 to 2.4) 0.178 Retired due to JIA

disability

1.0 (0.7 to 1.3) <0.001† 29.1 (19.9 to 38.3) <0.001† 1.4 (0.2 to 2.6) 0.028† Years of education‡ −0.0 (−0.1 to −0.0) 0.001† −0.1 (−0.9 to 0.7) 0.795 −0.1 (−0.2 to 0.1) 0.367 HAQ Score ‡ 12.5 (10.2 to 14.9) <0.001 † 1.1 (0.7 to 1.4) <0.001 † Duration of

corticosteroid

therapy ‡

0.0 (0.0 to 0.0) <0.001† 0.0 (0.0 to 0.0) 0.020† 0.0 (0.0 to 0.0) <0.001†

Exposure to

corticosteroids ‡

0.3 (0.2 to 0.5) <0.001 † 4.5 ( −1.1 to 10.2) 0.112 1.2 (0.5 to 1.9) 0.001 † Exposure to

biological DMARDs ‡

0.2 (0.0 to 0.3) 0.014 † 6.9 (1.3 to 12.5) 0.016 † 0.6 ( −0.1 to 1.3) 0.080 Exposure to synthetic

DMARDs ‡ −0.1 (−0.3 to 0.1)

0.394 −1.2 (−7.4 to 5.0) 0.699 −0.1 (−0.9 to 0.8) 0.864

†p Value <0.05.

*Compared to persistent oligoarticular.

‡Adjusted for ILAR category.

§Compared to non-classifiable.

¶Compared to employed.

ACPA, anticitrullinated protein antibodies; ANAs, antinuclear antibodies; AS, ankylosing spondylitis; ASD, adult Still disease; DMARDs, disease-modifying antirheumatic drugs; E oligoarthritis, extended oligoarthritis; EA, enteropathic arthritis; ERA, enthesitis-related arthritis; HAQ, Health Assessment Questionnaire; ILAR, International League of Associations for Rheumatology; JADI, Juvenile Arthritis Damage Index; JIA, juvenile idiopathic arthritis; PsA, psoriatic arthritis; RA, rheumatoid arthritis; RF, rheumatoid factor; RF+ polyarthritis, rheumatoid factor negative polyarthritis; RF+ polyarthritis, rheumatoid factor positive polyarthritis; SoJIA, systemic-onset juvenile idiopathic arthritis; Undif arthritis, undifferentiated arthritis; USpA, undifferentiated spondyloarthritis.

JIA, which have shown a tendency towards an improve-ment in the functional outcome of these patients over the last few years A decade ago JIA outcome studies described poorer functional outcomes, as in the Foster

et al27 study that found a median HAQ of 1.13 (0–3) or the Packham and Hall22 report that depicted severe dis-ability in 42% of the patients In our study, the mean HAQ was 0.52±0.68 and 11% of the patients had severe disability We found that higher HAQ was associated with longer disease duration and with polyarticular involve-ment at disease onset Unlike other studies,22 25 we did not notice a higher functional limitation in patients with SoJIA

The educational level of these patients was higher than the average for the Portuguese population, which was 7.4 years in 2014.28 However, the mean age of this study population (34.1 years) is lower than the mean age

of the Portuguese population (43.1 years),29 and school-ing has increased over recent years Malviyaet al30found

in a cohort of 103 patients with JIA, with a median disease duration of 19 years, that educational attainment was influenced by functional disability rather than by JIA category However, we did not found any strong associ-ation between HAQ and educassoci-ational level

Retirement due to disability was higher than the general Portuguese population, which was 3.4% in

2013.31 As expected, we found that retired patients due

to JIA disability had more articular damage than the ones who were employed The unemployed proportion

of patients was similar to the current Portuguese unemployment rate (11.8%).32

Longer disease duration and exposure to biological treatment were associated with higher JADI-A Longer disease duration and past or current treatment with cor-ticosteroids was also associated with higher JADI-E In a study of 87 patients with JIA followed up for a median of 4.0 years (2.0–5.2),33 the most pronounced deterioration

in JADI-A was observed in patients with SoJIA with pro-longed active disease In our study, not only SoJIA but also RF-positive and RF-negative polyarthritis onset were associated with higher JADI-A This is thefirst long-term study to analyse damage, measured by JADI in all cat-egories of JIA, and thus we have no comparable pub-lished data

Over the past three decades, some of the long-term outcome studies based on JIA cohorts attempted to identify early prognostic factors and predictors of a poor outcome.34–38In our study, younger age at disease onset was predictive of higher HAQ, JADI-A and JADI-E and decreased the chance of inactive disease in adulthood ACPA positivity decreased the likelihood of disease inactivity by 93.1% and RF-positive polyarthritis and SoJIA were predictive of a worse JADI-A, using persistent oligoarthritis as reference JIA persistent oligoarthritis, usually associated with a younger age at onset, was under-represented in this study This aspect could have

influenced our observation regarding the association between younger age of onset and worse prognosis

However, our findings were in line with other previous

studies For instance, Nordal et al26 observed that fewer

young onset children achieved disease remission off

medication as compared with children with late-onset

disease, independent of ILAR categories In a short-term

follow-up study, ACPA positivity seems to provide

predict-ive information on severity of disease course and

radio-logical outcome.39

Our study has some limitations First, its cross-sectional

design may not accurately estimate the overall disease

activity, as it missesfluctuations over time Second,

selec-tion bias of the registry may over-represent more severe

cases and some categories of JIA, as many patients in

remission could have been lost for follow-up

This study has also several strengths, as the long

follow-up and the use of validated disease activity adult

tools applied according to adult disease classification It

is also the first long-term study to evaluate how patients

fulfil classification criteria for adult rheumatic diseases

In fact, previous studies evaluated changing ILAR

cat-egories over time,26 34but fulfilment of criteria for adult

rheumatic diseases was never verified

This study shows that JIA represents a group of very

different diseases that evolve differently in adulthood

We found that most patients with JIA followed in adult

rheumatology clinics fulfilled classification criteria for

adult rheumatic diseases, maintain active disease and

functional impairment at long-term follow-up Younger

age at disease onset showed to be predictive of higher

HAQ, JADI-A and JADI-E and decreased the chance of

inactivity of the disease in adulthood

The results of this study are consistent with previous

criticisms to the current JIA classification and

nomencla-ture.40 Understanding the way these juvenile diseases

progress could add useful information for the ongoing

discussion of a new classification capable of better

unify-ing the language between paediatric and adult care

Author affiliations

Medical Center, Lisbon, Portugal

Medicina, Universidade de Lisboa, Lisbon, Portugal

Ocidental, Lisbon, Portugal

Delgada, Portugal

Coimbra, Portugal

de Lima, Portugal

Medicina da Universidade do Porto, Porto, Portugal

Acknowledgements The authors thank all patients and their families, as well

as all the rheumatologists and paediatricians who contributed to Reuma.pt

registry.

Contributors The corresponding author confirms that all the individuals listed

as authors fulfil the uniform authorship credit requirements for manuscripts submitted to medical journals as they all contributed to the manuscript based

on substantial contributions to conception and design, acquisition of data or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; final approval of the version to be published and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Competing interests None declared.

Ethics approval The study was reviewed and approved by scientific committee of Reuma.pt and by Ethics committee of Lisbon Academic Medical Centre Reuma.pt was approved by the National Committee for Data Protection and by local ethics committees of the participating centres.

Provenance and peer review Not commissioned; externally peer reviewed Data sharing statement No additional data are available.

Open Access This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial See: http:// creativecommons.org/licenses/by-nc/4.0/

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